RGS14 is a newly appreciated effector protein that integrates G protein and H- Ras/Raf1/ERK signaling pathways. RGS14 is a brain protein that is highly enriched in and largely restricted in its expression pattern to dendrites and spines of neurons of hippocampal region CA2. We recently discovered that RGS14 is critically important as a natural suppressor of synaptic plasticity (LTP) in CA2 neurons. Furthermore, we show that ectopic expression of RGS14 in CA1 neurons where RGS14 is not expressed blocks LTP there, suggesting that RGS14 engages common cell signaling pathways critical for synaptic plasticity. Unlike the well-studied CA1 region, very little is known about CA2 neurons or RGS14 there. The CA2 is implicated in human neurological diseases including schizophrenia, the autism/bipolar spectrum of disorders, and epilepsy. Mice lacking RGS14 (RGS14-KO) exhibit a marked and unexpected enhancement in spatial learning and object recognition memory compared with wild type littermates, but show no differences in non- hippocampal-dependent behaviors. RGS14-KO mice also exhibit a surprisingly robust nascent LTP with enhanced neuronal excitability at glutamatergic synapses in CA2, with no impact on plasticity in adjacent CA1 neurons. Together, these findings highlight the importance of understanding the molecular mechanism(s) whereby RGS14 regulates neuronal/synaptic plasticity. Within CA2/CA1 neurons, LTP expression and its suppression is due to both Ca++-dependent (CaM, CaMKII) and Ca++-independent (ERK, cAMP/PKA) mechanisms. RGS14 binds inactive Gi1/3-GDP and active H-Ras-GTP to form a heterotrimeric signaling complex that integrates G protein and MAPK signaling pathways. RGS14 also binds calmodulin (CaM) in a Ca++-dependent manner. These findings suggest RGS14 is well positioned to regulate plasticity in host neurons. Consistent with this idea, the nascent LTP in CA2 neurons following loss of RGS14 is dependent on MEK/ERK signaling. Based on this, my working hypothesis is that the Gi-GDP:RGS14:H-Ras-GTP signaling complex integrates G protein, MAPK and Ca++/CaM signaling pathways to serve as a natural suppressor of synaptic plasticity in host neurons. However, the molecular/structural basis for how RGS14 binds G proteins, H-Ras and CaM to operate as a signaling switch/integrator is unknown. Furthermore, the dynamic subcellular localization and regulation of native RGS14 in its natural host CA2 neurons, and the signaling pathways that the Gi1:RGS14: H-Ras signaling complex engages to regulate synaptic plasticity in host CA2/CA1 is entirely unknown. The Specific Aims are: AIM 1. Determine the structural basis and interdomain dynamics for how RGS14, Gi, H-Ras and CaM interact to form a functional signaling complex. AIM 2: Determine the cellular properties of native RGS14 and how RGS14 engages the H-Ras/ERK signaling pathway to regulate synaptic plastic in natural host CA2 neurons. AIM 3: Determine the signaling pathways used by the Gi:RGS14: H- Ras complex in CA2 or CA1 hippocampal neurons to regulate LTP in hippocampal slice preparations.